Throughout this application various publications are referred to in superscript. Full citations for these references may be found at the end of the specification. The disclosures of these publications are hereby incorporated by reference in their entirety into the subject application to more fully describe the art to which the subject invention pertains.
It is now recognized that many environmental toxicants (e.g., acrolein, chlorpyrifos methyl-mercury), as well as the endogenous mediators of cellular oxidative stress (e.g., free radicals, metal ions, unsaturated aldehydes), are electron deficient species (i.e., electrophiles). Substantial evidence indicates that these electrophilic toxicants cause cell damage by reacting with nucleophilic targets on biological macromolecules21, 37, 53, 55, 58, 59, 60, 62, 73, 83, 84. Thus, for example, α,β-unsaturated carbonyl/aldehyde compounds (type-2 alkenes) are an important class of environmental pollutants that includes acrolein, acrylamide and methyl vinyl ketone. Humans are pervasively exposed to these chemicals through natural sources, diet, industrial pollution and occupation, and the toxicological consequences of such exposures have been well documented14, 45, 58, 94. The common α,β-unsaturated carbonyl/aldehyde structure of the type-2 alkenes is a soft electrophile, and current evidence suggests that these chemicals cause toxicity by forming 1,4-Michael adducts with the soft nucleophilic thiolate state of protein sulfhydryl groups17, 22, 45, 56, 57, 61, 77.
Electrophilic species also play a prominent role in cellular oxidative stress, which is defined as an imbalance between the production of reactive oxygen species (ROS) and their removal via endogenous antioxidant systems. Oxidative stress is not only involved in the normal aging process, but is a pathogenic feature of many diseases (e.g., atherosclerosis, diabetes, Alzheimer's disease) and tissue injury states (e.g., spinal cord trauma, stroke). It is initiated by univalent reduction of molecular oxygen to form the superoxide anion radical. Subsequent dismutation via superoxide dismutase (SOD) yields hydrogen peroxide, which is converted via the metal ion (Cu, Fe)-catalyzed Fenton reaction to the highly toxic hydroxyl radical. This electron-deficient species can damage cells by direct interactions with macromolecules (e.g., DNA/RNA base oxidation, oxidative protein damage) and through membrane lipid peroxidation. Peroxidative fragmentation of polyunsaturated fatty acids (e.g., arachidonic and linoleic acids) generates lipid hydroperoxides that can undergo chain cleavage to yield toxic α,β-unsaturated aldehyde derivatives such as acrolein and 4-hydroxy-2-nonenal (HNE; reviewed in33, 42, 49, 59, 61, 81). These endogenous derivatives are highly reactive electrophiles that readily form adducts with nucleophilic sidechains on protein cysteines and other amino acid residues (e.g., see56, 52, 62; reviewed in28, 77, 94). Such protein adduct formation has been linked to broad cytotoxic consequences including inhibition of enzyme activity, mitochondrial dysfunction and disruption of cell signaling pathways. Accordingly, the “aldehyde burden” imposed by lipid peroxidation is now thought to be a critical pathogenic component of cellular oxidative stress5, 39, 69, 95, 96, 97 (reviewed in18, 27, 58, 60.) Oxidative stress can, therefore, be viewed as the sequential generation of electrophiles that mediate cell injury and death. Thus, electrophiles are a large class of endogenous and exogenous toxicants that play significant roles in pathophysiological processes.
Pharmacological treatment (e.g., N-aceyl cysteine) of many environmentally-derived toxicities (e.g., acrylamide contaminated well-water or industrial acrylonitrile poisoning) has often met with limited success. Moreover, many of the current pharmacotherapeutic venues (e.g., antioxidant therapy—α-tocopherol, β-carotene) available for treatment of certain disease states (e.g., Parkinson's disease) and traumatic injuries (e.g., spinal cord injury) are either palliative or have disappointing effectiveness. The complexity of the underlying etiologies is the likely explanation for the limited performance of these therapies. The research community almost uniformly agrees that the effective management of these pathogenic states will require either, a therapeutic “cocktail” involving several drugs or a multifunctional compound that can block the pathophysiological cascade at multiple rate-limiting steps. The present invention addresses the need for improved methods and compositions for treating subjects with diseases and tissue injury conditions that have cellular oxidative stress as a molecular etiology, such as atherosclerosis, diabetes, Alzheimer's disease, stroke and traumatic spinal cord injury, and for treating subjects with environmentally-derived toxicities.